Resolvin D1 Ameliorates Nicotinamide-streptozotocin-induced Type 2 Diabetes Mellitus by its Anti-inflammatory Action and Modulating PI3K/Akt/mTOR Pathway in the Brain

Abstract

To study whether resolvin D1 (RvD1), a metabolite of docosahexaenoic acid (DHA), prevents NA-STZ-induced type 2 diabetes mellitus (type 2 DM) invivo and if so, what could be the mechanism of this action. Single intra-peritoneal (i.p) injection of NA-STZ (175mg/kg body weight of NA and 65mg/kg of STZ) was injected simultaneously with RvD1 (60ng/animal) (injected for 5 consecutive days) to Wistar rats. The effect of RvD1 on plasma glucose levels and apoptotic (Bcl2/Bax) and inflammatory (NF-κB/iNOS) protein expression, plasma lipoxin A4 and BDNF (brain-derived neurotrophic factor) were studied. Protein expressions of PI3k-Akt-mTOR pathway along with histopathological studies of brain were also evaluated. NA-STZ-induced type 2 DM rats showed hyperglycemia, enhanced plasma IL-6/TNF-α (p ≤0.01), reduced plasma BDNF (p ≤0.01) and LXA4 (p ≤0.01) levels and low BDNF in pancreatic, hepatic and brain tissues (p <0.001), which were restored to near normal (p ≤0.01) in RvD1 treated group. RvD1 increased insulin sensitivity by suppressing inflammation (NF-κB/iNOS) (p ≤0.01) and decreasing apoptosis (Bcl2/Bax) and restoring BDNF and LXA4 levels to near normal. RvD1 treatment increased phosphorylation of Akt (Ser473), and subsequent activation (phosphorylation) of downstream signaling molecules of PI3K and mTOR indicating that RvD1 acts through PI3K/Akt/mTOR axis. RvD1 is effective in preventing NA-STZ-induced type 2 DM invivo by suppressing oxidative damage, enhancing the production of anti-inflammatory LXA4 and enhancing neuronal cell survival by augmenting the production of BDNF. Thus, RvD1 may be of benefit not only in preventing diabetes mellitus but also diabetes associated Alzheimer's disease and memory loss.